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Liposome formulation and manufacture

a technology of liposome and liposome, which is applied in the direction of liposomal delivery, medical preparations, pharmaceutical non-active ingredients, etc., can solve the problems of high large operating cost and time, and the size and shape of liposomal formulations known in the art are not substantially uniform, so as to reduce side effects, increase the degree of confidence in sterilization process, and the effect of size uniformity

Active Publication Date: 2018-06-12
ZULI HLDG LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The process results in liposomes that are highly uniform, stable, and effective, reducing adverse events and enabling efficient sterilization, while being cost-effective and suitable for large-scale production.

Problems solved by technology

These methods are limited to small-batch productions, primarily used for research purposes.
Moreover, the high pressure extrusion techniques are associated with high operating costs and time.
In addition, liposomal formulations known in the art are not substantially uniform in size and shape which is a critical feature of a pharmaceutical composition to provide a sterile product and avoid potentially toxic side effects of aberrant large liposomes.
Currently, it is difficult to manufacture a liposome formulation having a uniform size.
The extrusion process of multilamellar vesicles through a series of filters including, for example, 100 nm polycarbonate filters does not consistently produce a formulation having substantially uniform population of liposomes having a 100 nm size.
Moreover, many physical characteristics of the liposome formulation affect the cellular response to the liposome and impact the effectiveness of the liposome as a pharmaceutical composition.
However, the art does not address how the liposomal properties can be controlled in the formulation process to manipulate manufacturing efficiency and liposome stability.

Method used

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  • Liposome formulation and manufacture
  • Liposome formulation and manufacture
  • Liposome formulation and manufacture

Examples

Experimental program
Comparison scheme
Effect test

example 1

Formulation Batch Preparation

[0066]In accordance with the process described above, an example batch was prepared. Clearly the batch size may be varied, as desired for commercial production. In this example, a one liter batch of liposomal alendronate encapsulated in liposomes containing cholesterol, DSPC and DSPG, and dispersed in phosphate buffer saline solution was produced. Liposomal alendronate may be provided in two concentrations, for clinical convenience: 5 mg / ml and 0.5 mg / ml, as a sterile whitish, liposomal dispersion. These concentrations may be further formulated to obtain a desired amount of therapeutic agent in any specific volume. The lipid ingredients were composed of cholesterol, DSPC and DSPG. The dispersion also contained a phosphate buffer saline solution for pH control, infusion suitability and for the maintenance of isotonicity. At least 96% of the drug in the final product was encapsulated in the liposomes. For administration, the content of the vial (or part of...

example 2

Rigidity Testing

[0091]Four samples of large unilamellar liposomes (diameter approx. 100 nm) were analyzed for rigidity. Empty liposomes dissolved in PBS made in accordance with the present invention were labeled LPO. Liposome formulations containing 5.0 mg / ml of alendronate made in accordance with the present invention were labeled as LSA. Two other liposome samples, labeled KS and HU, dissolved in HEPES, were made in accordance with the prior art method described in Epstein-Barash, Hila, et al., “Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: Internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death”, J. Controlled Release 146 (2010) 182-195

[0092]Each sample was analyzed for specific volume compressibility of liposomes. Using ultrasound velocimetry, the elastic properties of the liposomes was evaluated based on the following relationship:

[0093]βS=1ρ·u2,(1)

where βS, ρ, and u are the adiab...

example 3

Stability Analysis

[0103]The stability of the liposome formulation made in accordance with Example 1 is exemplified in Tables 4 and 5. Table 4 demonstrates that the liposomes of the current invention are stable when stored at 4 degrees C. at least through 36 months, and the formulation meets all required specifications.

[0104]

TABLE 4Stability at 4 C.SpecBase1 Mo7 Mo12 Mo24 Mo36 MoappearancewhitishconformconformconformconformconformconformdispersionAlendronate0.5 ± 0.050.490.530.540.510.520.52(mg / ml)Encapsulation>9698%98%96>98%>99%>99%Percentage (%)DSPC (mg / ml)1.4-2.01.91.821.61.81.8DSPG (mg / ml)0.5-0.70.60.60.60.50.60.6Chol. (mg / ml)0.5-0.70.550.590.560.580.60.61drug:lipid ratio1:5.7 ± 1.0  1;6.21;5.61;5.91;5.31;5.81;5.8vesicles sizediameter92 nm92 nm92 nm92 nm91 nm91 nm(nm)100 ± 30 pH6.7-7.36.96.96.9776.9osmolality270-340309na317316312312(mo / kg)

[0105]Table 5 demonstrates that the liposomes of the current invention are stable when stored at 25 degrees C. at least through 7 months, and t...

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Abstract

The present invention relates to a liposomal formulation containing a therapeutic agent and a process for producing the formulation. The liposomal formulation comprises particular characteristics that enhance uniformity and stability of the formulation. The manufacturing process is a novel process that produces a liposomal formulation of a uniform size with many desirable properties that may be independently controlled. Further, the invention relates to a liposome formulation made in accordance with the manufacturing process.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a novel liposome formulation and a manufacturing process for the liposome formulation.BACKGROUND OF THE INVENTION[0002]Liposomes are known in the art to function as carriers to deliver therapeutic agents to targeted cells for treating a variety of medical conditions. In one application, liposomes may be formulated to encapsulate a pharmaceutical agent that can be phagocytized selectively by macrophages. Once phagocytized, the liposome releases the agent intracellularly, inhibiting inflammatory functions of the macrophages, among other effects.[0003]The art describes several methods for preparing such liposomes (see, e.g., Mönkkönen, J. et al., 1994, J. Drug Target, 2:299-308; Mönkkönen, J. et al., 1993, Calcif. Tissue Int., 53:139-145; Lasic D D., Liposomes Technology Inc., Elsevier, 1993, 63-105. (chapter 3); Winterhalter M, Lasic D D, Chem Phys Lipids, 1993; 54(1-3):35-43). In one such method, liposomes are formed into s...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K9/127A61K9/00A61K47/24
CPCA61K9/127A61K47/24A61K9/0019
Inventor RICHTER, YORAMZELIG, YEHUDAELMALAK, OMAREYAL, DROR
Owner ZULI HLDG LTD
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